US7439400B2 - Amino alcohol ligand and its use in preparation of chiral proparglic tertiary alcohols and tertiary amines via enantioselective addition reaction - Google Patents
Amino alcohol ligand and its use in preparation of chiral proparglic tertiary alcohols and tertiary amines via enantioselective addition reaction Download PDFInfo
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- US7439400B2 US7439400B2 US10/551,770 US55177005A US7439400B2 US 7439400 B2 US7439400 B2 US 7439400B2 US 55177005 A US55177005 A US 55177005A US 7439400 B2 US7439400 B2 US 7439400B2
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- 0 *C#C[C@@]([5*])([Rf])C1=CC=CC=C1CP.*C#C[C@]([5*])([Rf])C1=CC=CC=C1CP.C[Y].C[Y] Chemical compound *C#C[C@@]([5*])([Rf])C1=CC=CC=C1CP.*C#C[C@]([5*])([Rf])C1=CC=CC=C1CP.C[Y].C[Y] 0.000 description 14
- HFLPMPNXIQYYLW-XQKZEKTMSA-N CC.CC[C@@H](C)[C@H](O)C1=CC=CC=C1 Chemical compound CC.CC[C@@H](C)[C@H](O)C1=CC=CC=C1 HFLPMPNXIQYYLW-XQKZEKTMSA-N 0.000 description 5
- WJOMLFKHWPDQFE-PWSUYJOCSA-N CC[C@@H](C)[C@H](O)C1=CC=C(C)C=C1 Chemical compound CC[C@@H](C)[C@H](O)C1=CC=C(C)C=C1 WJOMLFKHWPDQFE-PWSUYJOCSA-N 0.000 description 4
- XNUQCJUZWXQODY-VXGBXAGGSA-N CC[C@H]([C@H](O)C1=CC=C([N+](=O)[O-])C=C1)N(C)C Chemical compound CC[C@H]([C@H](O)C1=CC=C([N+](=O)[O-])C=C1)N(C)C XNUQCJUZWXQODY-VXGBXAGGSA-N 0.000 description 4
- GSCVENBCKFRMLY-KCJUWKMLSA-N CC[C@@H](C)[C@H](O)C1=CC=C([N+](=O)[O-])C=C1 Chemical compound CC[C@@H](C)[C@H](O)C1=CC=C([N+](=O)[O-])C=C1 GSCVENBCKFRMLY-KCJUWKMLSA-N 0.000 description 3
- IXCOMAOTUBXVIW-VTLYIQCISA-N CC.N[C@H](CO)[C@H](O)C1=CC=CC=C1 Chemical compound CC.N[C@H](CO)[C@H](O)C1=CC=CC=C1 IXCOMAOTUBXVIW-VTLYIQCISA-N 0.000 description 2
- XPVNLTHVADPVIT-HZPDHXFCSA-N CN(C)[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](O)C1=CC=C([N+](=O)[O-])C=C1 Chemical compound CN(C)[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](O)C1=CC=C([N+](=O)[O-])C=C1 XPVNLTHVADPVIT-HZPDHXFCSA-N 0.000 description 2
- NGVBCXMCKVUQSZ-NRFANRHFSA-N COC1=CC=C(CN2C(=O)N[C@](C#CC3CC3)(C(F)(F)F)C3=CC(Cl)=CC=C32)C=C1 Chemical compound COC1=CC=C(CN2C(=O)N[C@](C#CC3CC3)(C(F)(F)F)C3=CC(Cl)=CC=C32)C=C1 NGVBCXMCKVUQSZ-NRFANRHFSA-N 0.000 description 2
- NKXFDQFVJBDDRE-UHFFFAOYSA-N C[Y].C[Y].O=C([Rf])C1=CC=CC=C1NP.O=C1N=C([Rf])C2=CC=CC=C2N1P Chemical compound C[Y].C[Y].O=C([Rf])C1=CC=CC=C1NP.O=C1N=C([Rf])C2=CC=CC=C2N1P NKXFDQFVJBDDRE-UHFFFAOYSA-N 0.000 description 2
- MWWATHDPGQKSAR-UHFFFAOYSA-N [H]C#CC Chemical compound [H]C#CC MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 2
- VGXPTFZWCZMNCF-UHFFFAOYSA-N C=C([Rf])C1=CC=CC=C1NP.C[Y] Chemical compound C=C([Rf])C1=CC=CC=C1NP.C[Y] VGXPTFZWCZMNCF-UHFFFAOYSA-N 0.000 description 1
- SHEUWOIRPHCIRP-UHFFFAOYSA-N C=C1N=C([Rf])C2=CC=CC=C2N1P.C[Y] Chemical compound C=C1N=C([Rf])C2=CC=CC=C2N1P.C[Y] SHEUWOIRPHCIRP-UHFFFAOYSA-N 0.000 description 1
- FPUVUYVKLYUIIU-UHFFFAOYSA-N COC1=CC=C(CN2C(=O)N=C(C(F)(F)F)C3=CC(Cl)=CC=C32)C=C1 Chemical compound COC1=CC=C(CN2C(=O)N=C(C(F)(F)F)C3=CC(Cl)=CC=C32)C=C1 FPUVUYVKLYUIIU-UHFFFAOYSA-N 0.000 description 1
- NOKSRMDODJGCPZ-UHFFFAOYSA-N NC1=CC=C(Cl)C=C1C(=O)C(F)(F)F Chemical compound NC1=CC=C(Cl)C=C1C(=O)C(F)(F)F NOKSRMDODJGCPZ-UHFFFAOYSA-N 0.000 description 1
- KEMUGFRERPPUHB-LBPRGKRZSA-N NC1=CC=C(Cl)C=C1[C@@](O)(C#CC1CC1)C(F)(F)F Chemical compound NC1=CC=C(Cl)C=C1[C@@](O)(C#CC1CC1)C(F)(F)F KEMUGFRERPPUHB-LBPRGKRZSA-N 0.000 description 1
- JJWJSIAJLBEMEN-ZDUSSCGKSA-N O=C(N[C@](C(F)(F)F)(c1c2)C#CC3CC3)Nc1ccc2Cl Chemical compound O=C(N[C@](C(F)(F)F)(c1c2)C#CC3CC3)Nc1ccc2Cl JJWJSIAJLBEMEN-ZDUSSCGKSA-N 0.000 description 1
- CQHQHKBAWKSJJE-LBPRGKRZSA-N O=C(N[C@](C1CCC1)(C(F)(F)F)c1c2)Nc1ccc2Cl Chemical compound O=C(N[C@](C1CCC1)(C(F)(F)F)c1c2)Nc1ccc2Cl CQHQHKBAWKSJJE-LBPRGKRZSA-N 0.000 description 1
- IGCMRUROJHFTCF-CHKLPSMSSA-N O=C1NC2=CC=C(Cl)C=C2[C@@](C#CC2CC2)(C(F)(F)F)N1.O=C1NC2=CC=C(Cl)C=C2[C@@](C=CC2CC2)(C(F)(F)F)N1.[AlH3].[LiH] Chemical compound O=C1NC2=CC=C(Cl)C=C2[C@@](C#CC2CC2)(C(F)(F)F)N1.O=C1NC2=CC=C(Cl)C=C2[C@@](C=CC2CC2)(C(F)(F)F)N1.[AlH3].[LiH] IGCMRUROJHFTCF-CHKLPSMSSA-N 0.000 description 1
- NPTDXPDGUHAFKC-UHFFFAOYSA-N [H]C#CC1CC1 Chemical compound [H]C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- the present invention relates to a process of asymmetric alkynylation of ketone or ketimine, particularly, the enantioselective addition of terminal alkynes to a trifluoromethyl ketone or ketimine intermediate to give a chiral tertiary proparglic alcohols or amines.
- the adduct compounds are the key precursors to the potent HIV reverse transcriptase inhibitor Efavirenz (DMP 266), DPC 961, and DPC 083.
- the present invention also relates to the novel amino alcohol ligand used in the process.
- HIV Human immunodeficiency virus
- DPC083, DPC 961, and Efavirenz are second generation HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency.
- Efavirenz SustivaTM has been approved for the treatment of HIV (Antimicrob. Agents Chemother. 1995, 39, 2602).
- DPC083 and DPC 961 are under clinical evaluation (Journal of Medicinal Chemistry vol. 43, no. 10, 2000, 2019-2030).
- the present invention relates to a new process of asymmetric alkynylation of ketone or ketimine.
- the invention also provide the new amino alcohol ligand used in the alkynylation process.
- a new process of asymmetric alkynylation of ketone or ketimine is disclosed, involving the enantioselective addition of terminal alkynes to a trifluoromethyl ketone or ketimine intermediate to give a chiral tertiary proparglic alcohols or amines.
- the adduct compounds are the key precursors to the potent HIV reverse transcriptase inhibitor Efavirenz (DMP 266), DPC 961 and DPC 083.
- reaction of zinc or copper acetylide with a trifluoromethyl ketone or ketimine produces an optically active product.
- this is achieved with a new chiral amino alcohol to mediate the addition reaction along an asymmetric pathway.
- the unusually high levels of optical activity (up to 99% ee) and very mild reaction condition make the method advantageous and practical.
- the chiral ligand can also be recycled.
- the process of the present invention uses an amino alcohol ligand as a catalyst for the asymmetric synthesis of the chiral compound of the structure
- Y is H mono- or multi-subsubstituted electron-withdrawing group or electron-donating group, preferably, H, mono- or di-subsubstituted electron-withdrawing group or electron-donating group, wherein Y can be located at in-, o-, or p-position of the benzene ring. More preferably, Y is H, Cl, Br, CH 3 SO 2 , CH 3 CH 2 SO 2 , NO 2 , or F. Most preferably, Y is F, Cl, Br. P is hydrogen or an amino protecting group.
- Rf is a fluoro-containing alkyl, preferably, a C 1 ⁇ C 20 fluoro-containing alkyl, and more preferably, a C 1 ⁇ C 4 fluoro-containing alkyl.
- R is a trialkylsilyl, alkyl, cycloalkyl or aryl group.
- R 6 is hydrogen when R 5 is hydroxyl of the structure:
- R 5 and R 6 can be cyclization such as —HNCO— of the structure
- the above amino alcohol ligand is of the structure
- R 1 , R 2 is amino protecting group
- R 1 , R 2 is the same or different group
- the above reaction is quenched by adding a proton source to give the desired compound.
- the proton source is a saturated aqueous solution of NH 4 Cl, water, aqueous hydrochloric acid or citric acid.
- the amino alcohol ligand is a compound of the structure
- R 1 , R 2 , R 3 , Z is the same as above.
- the chiral ligand is a compound of the structure or its enatiomer
- R 1 , R 2 , R 4 , Z is the same as above.
- the chiral ligand is a compound of the structure or its enatiomer
- R 1 , R 2 , R 4 , Z is the same as above.
- this invention provides a novel process for making a compound of the structure or its enatiomer
- the chiral ligand is a compound of the structure or its enatiomer
- R 1 , R 2 , R 4 is the same as above; preferrably, R 1 , R 2 is Me.
- the chiral ligand is a compound of the structure or its enatiomer
- the chiral ligand is a compound of the structure or its enatiomer
- the chiral ligand is a compound of the structure or its enatiomer
- the stoichiometric ratios are about 0.1-3 equivalent molar of ligand to substrate ketone or ketimine.
- the stoichiometric ratios are about 0.5-3 equivalent molar of ligand to substrate ketone or ketimine.
- the stoichiometric ratios are about 1.2-1.5 equivalent molar of ligand to substrate ketone or ketimine.
- the stoichiometric ratios are about 0.1-3 equivalent molar of terminal alkyne to substrate ketone or ketimine.
- the stoichiometric ratios are about 0.5-3 equivalent molar of terminal alkyne to substrate ketone or ketimine.
- the stoichiometric ratios are about 1.2-1.5 equivalent molar of terminal alkyne to substrate ketone or ketimine.
- the metal salts is selected from ZnCl 2 , ZnBr 2 , ZnF 2 , ZnI 2 , Zn(OTf) 2 , Zn(SO 3 CF 2 H) 2 , CuCl 2 , CuBr 2 , Cu(OTf) 2 , CuCl, CuBr, Cu(OTf), CuI.
- the Zinc(II) or Cu(II) salts is Zn(OTf) 2 or Cu(OTf) 2 .
- the Zinc(II) is Zn(OTf) 2 .
- the stoichiometric ratios are about 0.1-3 equivalent molar of the Zinc(II) salt or Cu salt to substrate ketone or ketimine.
- the stoichiometric ratios are about 0.5-3 equivalent molar of the Zinc(II) salt or Cu salt to substrate ketone or ketimine.
- the stoichiometric ratios are about 1.2-1.5 equivalent molar of the Zinc salt or Cu salt to substrate ketone or ketimine.
- the stoichiometric ratios are about 1.0-4.0 equivalent molar of the organic base to substrate ketone or ketimine.
- the stoichiometric ratios are about 2.0 ⁇ 3.5 equivalent molar of the organic base to substrate ketone or ketimine.
- organic base is selected from MeN(iPr) 2 , HNEt 2 , N(iPr) 3 , pyridine, NEt 3 , piperidine, NBu 3 , EtN(iPr) 2 .
- reaction is carried out in aprotic solvent or ethereal solvent.
- aprotic solvent include THF, dioxane, CH 2 Cl 2 Et 2 O, benzene, DME, toluene, n-hexane, and cyclohexane, or mixture thereof.
- solvent is toluene.
- reaction temperature is between about 0° C. and about 100° C.
- reaction temperature is between about 0° C. and about 50° C., especially at room temperature.
- R 1 and R 2 is alkyl, substituted alkyl, benzyl or substituted benzyl or trialkysily protected groups
- the substituted group can be phenyl, naphenyl, halo, nitro, hydroxy, C 1 ⁇ C 3 hydroxy alkyl, C 1 ⁇ C 4 alkyl, C 1 ⁇ C 3 alkoxy, CN; or R 1 , R 2 can be —(CH 2 ) n X(CH 2 ) m —, where X can be CH 2 , O or NH; n,m is an integer from 1 to 6.
- P is hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl or trialkylsilyl protected groups, the substituted group can be phenyl, naphenyl, halo, nitro, hydroxy, C 1 ⁇ C 3 hydroxyalkyl, C 1 ⁇ C 4 alkyl, C 1 ⁇ C 3 alkoxy, CN;
- R 4 is alkyl, substituted alkyl, benzyl or substituted benzyl or trialkylsilyl, the substituted group can be phenyl, naphenyl, halo, nitro, hydroxy, C 1 ⁇ C 3 hydroxy alkyl, C 1 ⁇ C 4 alkyl, C 1 ⁇ C 3 alkoxy, CN;
- electronwithdrawing group is halogen, NO 2 , CF 3 , CH 3 S 2 , CH 3 CH 2 SO 2 , PhCH 2 OCO, or AcO.
- electron-donating group is alkoxy (especially C 1 ⁇ C 3 alkoxy), OH, Me 2 NCH 2 CH 2 O, Et 2 NCH 2 CH 2 O, NH 2 , alkyl (especially C 1 ⁇ C 4 alkyl).
- R 1 and R 2 is C 1 ⁇ C 20 alkyl, C 1 ⁇ C 20 substituted alkyl, benzyl, substituted benzyl or C 1 ⁇ C 20 trialkylsilyl protected groups
- the substituted group is the same as above; or
- R 1 , R 2 can be —(CH 2 ) n X(CH 2 ) m —, where X can be CH 2 , O or NH; n,m is an integer from 1 to 6.
- P is hydrogen, C 1 ⁇ C 20 alkyl, C 1 ⁇ C 20 substituted alkyl, benzyl or substituted benzyl or C 1 ⁇ C 20 trialkylsilyl protected groups, the substituted group is the same as above;
- R is C 1 ⁇ C 20 trialkylsilyl, C 1 ⁇ C 20 alkyl, C 3 ⁇ C 20 cycloalkyl or aryl, the aryl is phene, naphthalene, furan, thiophene, pyrrole.
- R 3 is C 1 ⁇ C 20 alkyl; C 1 ⁇ C 20 alkyl substituted with alkyloxy or silyoxy, carboxylic group, C 1 ⁇ C 20 carbalkoxy group, hydroxyl methyl, C 3 ⁇ C 20 cycloalkyl, aryl or CH 2 OR 4 , wherein R 4 is C 1 ⁇ C 20 alkyl, C 1 ⁇ C 20 substituted alkyl, benzyl or substituted benzyl or C 1 ⁇ C 20 trialkylsilyl, the substituted group is the same as above.
- Z is H, F, Cl, Br, I, CH 3 SO 2 OH, PhCH 2 O, AcO, MeO, EtO, Me 2 NCH 2 CH 2 O, Et 2 NCH 2 CH 2 O, PhCH 2 OCO, t-Bu, i-Pr, NH 2 , or NO 2 ;
- Y is H, F, Cl, Br, I, CH 3 SO 2 OH, PhCH 2 O, AcO, MeO, EtO, Me 2 NCH 2 CH 2 O, Et 2 NCH 2 CH 2 O, PhCH 2 OCO, t-Bu, i-Pr, NH 2 , or NO 2 ;
- R 1 and R 2 is C 1 ⁇ C 4 alkyl, tri-phenyl methyl, t-butyldimethylsilyl, benzyl unsubstituted or substituted with C 1 ⁇ C 4 alkyl; para-methoxy benzyl; para-nitrobenzyl; para-chlorobenzyl; 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl; or N-trialkylsilyl groups; or R 1 , R 2 can be —(CH 2 ) 2 O(CH 2 ) 2 —, —(CH 2 ) 2 N(CH 2 ) 2 —, —(CH 2 ) 5 — or —(CH 2 ) 6 —.
- P is hydrogen, C 1 ⁇ C 4 alkyl, tri-phenyl methyl, t-butyldimethylsilyl, benzyl unsubstituted or substituted with C 1 ⁇ C 4 alkyl; para-methoxy benzyl; para-nitrobenzyl; para-chlorobenzyl; 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl;
- R is C 1 ⁇ C 4 alkyl, C 3 ⁇ C 6 cycloalkyl or aryl, the aryl is phene, naphthalene, furan, thiophene, pyrrole.
- R 3 is C 1 ⁇ C 4 alkyl; C 1 ⁇ C 4 alkyl substituted with alkyloxy or silyoxy, carboxylic group, C 1 ⁇ C 4 carbalkoxy group, hydroxyl methyl, C 3 ⁇ C 6 cycloalkyl, aryl or CH 2 OR 4 , wherein R 4 is C 1 ⁇ C 4 alkyl, tri-phenyl methyl, t-butyldimethylsilyl, benzyl unsubstituted or substituted with C 1 ⁇ C 4 alkyl; para-methoxy benzyl; para-nitrobenzyl; para-chlorobenzyl; 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl;
- Y is H, Cl, Br, CH 3 SO 2 , CH 3 CH 2 SO 2 , NO 2 or F;
- Halogen or halo is fluoro, chloro, bromo and iodo.
- the present invention provides a novel chiral ligand or its enatiomer having the structure as follows:
- R 1 , R 2 is amino protecting group
- R 1 , R 2 is the same or different group
- R 1 , R 2 is C 1 -C 4 alkyl(such as methyl), benzyl unsubstituted or substituted with C 1 -C 4 alkyl; para-methoxy benzyl; para-nitrobenzyl; para-chlorobenzyl; 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl; or trialkylsilyl group; or R 1 , R 2 can be —(CH 2 ) 2 O(CH 2 ) 2 —, —(CH 2 ) 2 N(CH 2 ) 2 —, —(CH 2 ) 5 — or —(CH 2 ) 6 —.
- R 4 is C 1 -C 4 alkyl (such as butyl), benzyl unsubstituted or substituted with C 1 -C 4 alkyl; para-methoxy benzyl; para-nitrobenzyl; para-chlorobenzyl; 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl; or trialkylsilyl group which exclude t-Butyldimethylsilyl.
- Z is Cl, Br, NO 2 , CF 3 , CH 3 SO 2 , CH 3 CH 2 SO 2 , CH 3 O, OH or C 1 ⁇ C 4 alkyl, especially Z is CH 3 SO 2 or NO 2 ;
- R 1 is N ⁇ O
- R 2 is COCH 3
- R 4 is only alkyl, substituted alkyl, benzyl substituted benzyl, or trialkylsilyl
- R 1 , R 2 is CH 3 , R 4 is only alkyl, substituted alkyl, benzyl substituted benzyl; said substituted group is the same as above;
- novel chiral ligand is a compound of the structure or its enatiomer
- R 1 , R 2 , R 4 , Z is the same as above.
- novel chiral ligand is a compound of the structure or its enatiomer
- R 1 , R 2 , R 4 is the same as above, preferably, R 1 , R 2 is Me.
- the novel chiral ligand is a compound of the structure or its enatiomer
- the novel chiral ligand is a compound of the structure or its enatiomer
- the novel chiral ligand is a compound of the structure or its enatiomer
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; if the number of carbon atoms is unspecified, “alkyl” is intended to include 1 to 20 carbon atoms, preferred is 1 to 4 carbon atoms, both branched and straight-chain saturated aliphatic hydrocarbon groups. For example, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl.
- Halogen or “halo” as used herein, means fluoro, chloro, bromo and iodo.
- alkoxyl is intended to include both branched- and straight-chain groups having the specified number of carbon atoms; if the number of carbon atoms is unspecified, “alkoxyl” is intended to include 1 to 20 carbon atoms, preferred is 1 to 4 carbon atoms.
- cycloalkyl is intended to include 3 to 20 carbon atoms, preferred is 3 to 6 carbon atoms.
- aryl is intended to include phenyl, naphenyl, furan, thiophene , pyrrole, preferred is phenyl.
- “carbalkoxy group” is intended to include 1 to 20 carbon atoms, preferred is 1 to 4 carbon
- R 1 and R 2 is the same or different group.
- R 1 and R 2 is any suitable amino protecting group, and includes, but is not limited to, alkyl, substituted alkyl (the substituted group can be phenyl, naphenyl, halo, nitro, hydroxy, C 1 ⁇ C 3 hydroxy, alkyl, C 1 ⁇ C 3 alkoxy, CN), benzyl, substituted benzyl(the substituted group can be phenyl, naphenyl, halo, nitro, hydroxy, C 1 ⁇ C 3 hydroxy, alkyl, C 1 ⁇ C 3 alkoxy) or trialkylsilyl, or R 1 , R 2 can be —(CH 2 ) n X(CH 2 ) m —, where X can be CH 2 , O or NH; n,m is an integer from 1 to 6.
- R 1 or R 2 is C 1 ⁇ C 4 alkyl, tri-phenyl methyl, t-butyldimethylsilyl, benzyl unsubstituted or substituted with C 1 ⁇ C 20 alkyl; para-methoxy benzyl; para-nitrobenzyl; para-chlorobenzyl; 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl; preferred is C 1 -C 4 alkyl, benzyl unsubstituted or substituted with C 1 -C 4 alkyl; para-methoxy benzyl; para-nitrobenzyl; para-chlorobenzyl; 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl; or R 1 , R 2 can be —(CH 2 ) 2 O(CH 2 ) 2 —, —(CH 2 ) 2 N(CH 2 ) 2 —, —(CH 2 ) 5 — or —(CH 2
- P is hydrogen or any suitable amino protecting group described as above.
- R 4 is any suitable oxygen protecting group, and includes, but is not limited to, alkyl, substituted alkyl, benzyl or substituted benzyl or trialkylsilyl protected groups. Preferred is C 1 ⁇ C 20 alkyl unsubstituted or substituted, benzyl unsubstituted or substituted, or trialkylsilyl protected groups.
- the substituted group can be phenyl, naphenyl, halo, nitro, hydroxy, C 1 ⁇ C 3 hydroxyalkyl, C 1 ⁇ C 3 alkoxy, CN.
- R 3 is C 1 ⁇ C 4 alkyl, tri-phenyl methyl, t-butyldimethylsilyl, benzyl unsubstituted or substituted with C 1 -C 4 alkyl; para-methoxy benzyl; para-nitrobenzyl; para-chlorobenzyl; 2,4-dichlorobenzyl; 2,4-dimethoxybenzyl; or trialkylsilyl groups.
- Other protective groups are according to T. W. Greene et al., Protective groups in Organic Synthesis 3rd Ed. John Wiley 1999, pp. 17-245.
- a preferable oxygen protecting group is t-butyl.
- electronwithdrawing group includes, but is not limited to, halogen, NO 2 , CF 3 , CH 3 SO 2 , CH 3 CH 2 SO 2 , PhCH 2 OCO or AcO.
- Electron-donating group includes, but is not limited to, alkoxy especialy C 1 ⁇ C 20 alkoxy, OH, Me 2 NCH 2 CH 2 O, Et 2 NCH 2 CH 2 O, NH 2 , alkyl.
- Example of the reductant can be formic acid, NaBH 4 , KBH 4 , LiAlH 4 or Pd/C.
- the amino group at 2-position also can be protected by reaction with R 1 X or R 2 X in organic solvent in the presence of base, wherein X is halogen.
- the hygroxy group at 3-position can be protected with t-butyl by reaction with iso-butene catalydzed by acid.
- the hygroxy group at 3-position also can be protected with R 3 by reaction with R 3 X, wherein X is halogen.
- the above reaction condition can be routine.
- Said base can be inorganic base or organic base, for example, K 2 CO 3 , Na 2 CO 3 , NaOH, KOH or NEt 3 .
- organic solvent can be alcohol, alkyl substituted by halogen or ether.
- Example of the protection detail is refluxing with formaldehyde and formic acid to protect amino group with di-methyl, or reacting with benzaldehyde for condensation and then reducing by NaBH4 to protect the amino group by benzyl group.
- Efavirenz, DPC 961 and DPC 083 can be synthesized by the following method.
- the present invention provides a novel ligand.
- the use of the ligand relates to asymmetric addition, particularly, a direct synthesis of the optically active DPC 961, DPC083, and efavirenz by chiral addition of zinc or copper acetylide to a ketimine intermediate to give a proparglic amine, with enantiomeric excess up to 99%, or by chiral addition of zinc or copper acetylide to an ketone intermediate to give a proparglic alcohol.
- the process of the present invention provides a chiral amino alcohol to mediate the addition reaction along an asymmetric pathway.
- the previous methods of derivatization and fractional crystallization or 1,4-diastereoselective addition protocol both employ an auxiliary ( Journal of Organic Chemistry vol. 68, no. 3, 2003, 754-761 ; Tetrahe - dron Letter vol. 41, 2000, 3015-3019).
- WO 200170707 discloses an asymmetric process for preparing DPC961 via chiral moderated asymmetric addition.
- the process uses a large amount of excess strong base (lithium alkyl and LHMDS) and excess chiral ligand was-used under very strict condition ( ⁇ 20° C.), while the process of the present invention can be performed with very mild reaction condition (20-40° C.).
- the ligand used in the reaction of the present invention is less expensive.
- the ligand in the reaction of the present invention can be recycled.
- the workup is also very simple. All of the advantages render the reduction of the cost of the process greatly.
- reaction of zinc or copper acetylide with a trifluoromethyl ketimine produces an optically active product.
- the invention not only provide a kind of novel ligand in the enantioselective alkynylation of ketimine, but also provide a practical industrial process of preparation DPC 961. In the present invention, this is achieved with a chiral amino alcohol to mediate the addition reaction along an asymmetric pathway.
- the unusually high levels of optical activity (up to 99% ee) and very mild reaction condition make the method advantageous and practical.
- the 4-chloro-2-trifluoroacetyl aniline (2.23 g, 10 mmol) was added in one port. The mixture was stirred at 25° C. for 10 hr. The resulting solution was quenched by adding saturated citric acid aqueous solution. The mixture was extracted with EtOAc. The aqueous was saved for the recovery of ligand. The combined organic layers was dried with Na 2 SO 4 and concentrated in vacuo. Heptane was added to the mixture slowly. The white solid was collected by filtration, and dried to give the adduct product (60% yield, 90.1% ee).
- the 4-chloro-2-trifluoroacetyl aniline (2.23 g, 10 mmol) was added in one port. The mixture was stirred at 25° C. for 10 hr. The resulting solution was quenched by adding saturated citric acid aqueous solution. The mixture was extracted with EtOAc. The aqueous was saved for the recovery of ligand. The combined organic layers was dried with Na 2 SO 4 and concentrated in vacuo. Heptane was added to the mixture slowly. The white solid was collected by filtration, and dried to give the adduct product (60% yield, 99.1% ee).
- the 4-chloro-2-trifluoroacetyl aniline (2.23 g, 10 mmol) was added in one port. The mixture was stirred at 25° C. for 10 hr. The resulting solution was quenched by adding NH 4 Cl aqueous solution. The mixture was extracted with EtOAc. The aqueous was saved for the recovery of ligand. The combined organic layers was dried with Na 2 SO 4 and concentrated in vacuo. Heptane was added to the mixture slowly. The white solid was collected by filtration, and dried to give the adduct product (51% yield, 96.1% ee).
- the p-methoxybenzyl protected ketimine (3.69 g, 10 mmol) was added in one port. The mixture was stirred at 25° C. for 10 hr. The resulting solution was quenched by adding saturated citric acid aqueous solution. The mixture was extracted with EtOAc. The aqueous was saved for the recovery of ligand. The combined organic layers was dried with Na 2 SO 4 and concentrated in vacuo. Heptane was added to the mixture slowly. The white solid was collected by filtration, and dried to give the product (95% yield, 99.3% ee).
- DPC 961 The p-methoxybenzyl protected DPC 961 (2 mmol) was dissolved in 10% aqueous CH 3 CN (10 mL), and ceric ammonium nitrate (4.4 g, 8 mmol) was added. After stirring for 4 hr at 25° C., the reaction was diluted with water and extracted with EtOAc. The combined organic layer was concentrated in vacuo to afford DPC 961 in 80% yield.
- the p-methoxybenzyl protected ketimine (3.69 g, 10 mmol) was added in one port. The mixture was stirred at 25° C. for 10 hr. The resulting solution was quenched by adding saturated citric acid aqueous solution. The mixture was extracted with EtOAc. The aqueous was saved for the recovery of ligand. The combined organic layers was dried with Na 2 SO 4 and concentrated in vacuo. Heptane was added to the mixture slowly. The white solid was collected by filtration, and dried to give the product (81% yield, 97.1% ee).
- the p-methoxybenzyl protected ketimine (3.69 g, 10 mmol) was added in one port. The mixture was stirred at 25° C. for 10 hr. The resulting solution was quenched by adding saturated citric acid aqueous solution. The mixture was extracted with EtOAc. The aqueous was saved for the recovery of ligand. The combined organic layers was dried with Na 2 SO 4 and concentrated in vacuo. Heptane was added to the mixture slowly. The white solid was collected by filtration, and dried to give the product (31% yield, 63.1% ee).
Abstract
Description
where Y is H mono- or multi-subsubstituted electron-withdrawing group or electron-donating group, preferably, H, mono- or di-subsubstituted electron-withdrawing group or electron-donating group, wherein Y can be located at in-, o-, or p-position of the benzene ring. More preferably, Y is H, Cl, Br, CH3SO2, CH3CH2SO2, NO2, or F. Most preferably, Y is F, Cl, Br. P is hydrogen or an amino protecting group.
- R3 is alkyl, substituted alkyl (substituted group can be alkyloxy or silyoxy, especially), carboxylic group, carbalkoxy group, hydroxy methyl, cycloalkyl, aryl or CH2OR4; wherein
- R4 is an oxygen protecting group,
- Z is H, mono or multisubstituted electronwithdrawing group or electron-donating group, preferred is H, mono or di-subsubstituted electronwithdrawing group or electron-donating group, wherein Z can be located at m-, o-, or p-positon of the benzene ring; More preferable is H, F, Cl, Br, I, CH3SO2OH, PhCH2O, AcO, MeO, EtO, Me2NCH2CH2O, Et2NCH2CH2O, PhCH2OCO, t-Bu, i-Pr, NH2, or NO2;
The process comprises the steps of: - (a) providing a mixture of chiral ligand (1R,2R)-2-N,N-substituted-1-(substituted-phenyl)-2-R3-substituted-2-aminoethanol or its enantiomer, of the structure
- with a terminal alkyne and a Zn(II), Cu(II) or Cu(I) salts in the presence of an organic base in organic solvent, wherein the terminal alkyne is
- R is the same as above.
- (b) mixing with the mixture of step (a) of reactant of the structure
- wherein P, Rf, Y is the same as above;
- (a) providing a mixture of 0.1˜3 molar equivalent of a chiral ligand (1R,2R)-2-N,N-substitutedamino-1-(4-substituted-phenyl)-3-O-substituted-propane-1-ol, of the structure or its enatiomer,
- wherein Z, R1, R2, R4 is the same as above,
- with 0.1˜3 molar equivalent of a terminal alkyne and 0.1˜3 molar equivalent of Zn(II), Cu(I)or Cu(II) salts in the presence of 1˜4 molar equivalent of an organic base in organic solvent, the terminal alkyne is
- (b) mixing with the mixture of step (a) of 1.0 molar equivalent of reactant of the structure
- or of the structure that is the 4-methoxybenzyl protected ketimine(I):
- preferably, maintaining the resulting reaction mixture at a temperature of between about 0-50° C., especially at room temperature for 1-20 hr; quenching by adding a proton source to give the desired compound.
- R4 is oxygen protecting group,
- Z is mono or multisubstituted electronwithdrawing group or electron-donating group, wherein Z can be located at m-, o-, or p-positon of the benzene ring.
- Preferably, R1 and R2 is alkyl, substituted alkyl, benzyl, substituted benzyl, or trialkylsilyl group; or R1, R2 can be —(CH2)nX(CH2)m—, where X can be CH2, O or NH; n, m is an integer from 1 to 6.
- R4 is alkyl, substituted alkyl, benzyl, substituted benzyl, or trialkylsilyl group; Example of the substituted group of alkyl or benzyl is phenyl, naphthyl, halogen, hydroxy, NO2, C1˜C3 alkoxy, CN;
- Z is halogen, NO2, CF3, CH3SO2, CH3CH2SO2, CH3O, OH or alkyl;
- Preferably, Z is mono or multisubstituted electronwithdrawing group or electron-donating group, more preferably Z is F, Cl, Br, I, CH3SO2OH, PhCH2O, AcO, MeO, EtO, Me2NCH2CH2O, Et2NCH2CH2O, PhCH2OCO, t-Bu, i-Pr, NH2, or NO2
- More preferably, R1, R2 is C1˜C20 alkyl, C1-C20 substituted alkyl, benzyl, substituted benzyl, C1-C20 trialkylsilyl group; or R1, R2 can be —(CH2)nX(CH2)m—, where X can be CH2, O or NH; n,m is an integer from 1 to 6.
- R4 is C1-C20 alkyl, C1-C20 substituted alkyl, benzyl, substituted benzyl, or C1-C20 trialkylsilyl group;
or its enantiomer. The hygroxy group at 3-position and amino at 2-position group was protected according to T. W. Greene et al., Protective groups in Organic Synthesis 3rd Ed. John Wiley 1999.
can be protected first by condensation of corresponding aldehyde then by reducing in organic solvent. Example of the reductant can be formic acid, NaBH4, KBH4, LiAlH4 or Pd/C. The amino group at 2-position also can be protected by reaction with R1X or R2X in organic solvent in the presence of base, wherein X is halogen. The hygroxy group at 3-position can be protected with t-butyl by reaction with iso-butene catalydzed by acid. The hygroxy group at 3-position also can be protected with R3 by reaction with R3X, wherein X is halogen. The above reaction condition can be routine. Said base can be inorganic base or organic base, for example, K2CO3, Na2CO3, NaOH, KOH or NEt3. Example of said organic solvent can be alcohol, alkyl substituted by halogen or ether. Example of the protection detail is refluxing with formaldehyde and formic acid to protect amino group with di-methyl, or reacting with benzaldehyde for condensation and then reducing by NaBH4 to protect the amino group by benzyl group.
Claims (21)
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CN 03116192 CN1216036C (en) | 2003-04-04 | 2003-04-04 | Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine |
CN03116192.8 | 2003-04-04 | ||
CN03117026.9 | 2003-05-16 | ||
CNB031170269A CN1331601C (en) | 2003-05-16 | 2003-05-16 | Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone |
PCT/CN2003/000462 WO2004087628A1 (en) | 2003-04-04 | 2003-06-16 | An amino alcohol ligand and its use in preparation of chiral proparglic tertiary alkohols and tertiary amines via enantioselective additon reaction |
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US20060217552A1 US20060217552A1 (en) | 2006-09-28 |
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US (1) | US7439400B2 (en) |
EP (1) | EP1614672B1 (en) |
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WO (1) | WO2004087628A1 (en) |
Cited By (4)
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EP2235023A2 (en) | 2008-01-31 | 2010-10-06 | Aptuit Laurus Private Limited | An efficient process to induce enantioselectivity in procarbonyl compounds |
US20110015189A1 (en) * | 2009-07-20 | 2011-01-20 | Apotex Pharmachem Inc. | Methods of making efavirenz and intermediates thereof |
US20120264933A1 (en) * | 2008-01-31 | 2012-10-18 | Laurus Labs Private Limited | Efficient process to induce enantioselectivity in procarbonyl compounds |
US10214480B2 (en) * | 2015-02-15 | 2019-02-26 | Shanghai Desano Pharmaceutical Co., Ltd. | Synthesis process for chiral cyclopropyl ethynyl tertiary alcohol compound |
Families Citing this family (4)
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EP2417097A2 (en) | 2009-04-09 | 2012-02-15 | Lonza Ltd. | Autocatalytic process for the synthesis of chiral propargylic alcohols |
US8115032B2 (en) * | 2009-04-09 | 2012-02-14 | Lonza Ltd. | Process for the synthesis of a propargylic alcohol |
EP2448917A2 (en) | 2009-07-03 | 2012-05-09 | Archimica GmbH | Method for the enantioselective addition of organometallic carbon nucleophiles to trifluoromethyl ketones and use of the method in the synthesis of hiv reverse transcriptase inhibitors |
CN102180915B (en) * | 2011-03-25 | 2014-08-13 | 南京理工大学 | D-fructopyranose derived saccharide beta-alkamine and synthesis method thereof |
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- 2003-06-16 US US10/551,770 patent/US7439400B2/en not_active Expired - Fee Related
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2235023A2 (en) | 2008-01-31 | 2010-10-06 | Aptuit Laurus Private Limited | An efficient process to induce enantioselectivity in procarbonyl compounds |
US20100286408A1 (en) * | 2008-01-31 | 2010-11-11 | Aptuit Laurus Pvt. Ltd. | efficient process to induce enantioselectivity in procarbonyl compounds |
US20120264933A1 (en) * | 2008-01-31 | 2012-10-18 | Laurus Labs Private Limited | Efficient process to induce enantioselectivity in procarbonyl compounds |
US9073817B2 (en) * | 2008-01-31 | 2015-07-07 | Laurus Labs Private Limited | Efficient process to induce enantioselectivity in procarbonyl compounds |
US9156756B2 (en) * | 2008-01-31 | 2015-10-13 | Laurus Labs Private Limited | Efficient process to induce enantioselectivity in procarbonyl compounds |
US20110015189A1 (en) * | 2009-07-20 | 2011-01-20 | Apotex Pharmachem Inc. | Methods of making efavirenz and intermediates thereof |
US10214480B2 (en) * | 2015-02-15 | 2019-02-26 | Shanghai Desano Pharmaceutical Co., Ltd. | Synthesis process for chiral cyclopropyl ethynyl tertiary alcohol compound |
Also Published As
Publication number | Publication date |
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AU2003248217A1 (en) | 2004-10-25 |
WO2004087628A1 (en) | 2004-10-14 |
EP1614672A4 (en) | 2007-04-04 |
EP1614672A1 (en) | 2006-01-11 |
EP1614672B1 (en) | 2010-09-22 |
US20060217552A1 (en) | 2006-09-28 |
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